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The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis.

Üner A, Gonçalves GH, Li W, Porceban M, Caron N, Schönke M, Delpire E, Sakimura K, Bjørbæk C - Mol Metab (2015)

Bottom Line: NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function.We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control.Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

ABSTRACT

Objective: Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown.

Methods: We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies.

Results: We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lep (ob/ob) mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lep (ob/ob) mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions.

Conclusions: GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action.

No MeSH data available.


Related in: MedlinePlus

Elimination of GluN2B in AgRP neurons of Lepob/obmice normalizes hyperglycemia independently body weight. (A–D) Body weight (A), body composition (8 weeks of age) (B), average daily food intake (week 7–8) (C), and blood glucose (D) in ob/ob controls (ob/ob;AgRP-ires-cre and ob/ob;GluN2Bflox/flox) and ob/ob;AgRP-GluN2B KO female mice. (E and F) Body weight (E) and food intake (F) of female mice (9 weeks of age) after implantation of osmotic pumps loaded with leptin (500 ng/h) (9 days). Values in E and F are shown as percent of initial body weight and food intake, respectively. Data are shown as means ± SEM (n = 3–12 mice/group). Repeated measures two-way ANOVA or Student's t test were conducted to evaluate differences between groups. *P ≤ 0.05, **P ≤ 0.01. NS: Not significant.
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fig6: Elimination of GluN2B in AgRP neurons of Lepob/obmice normalizes hyperglycemia independently body weight. (A–D) Body weight (A), body composition (8 weeks of age) (B), average daily food intake (week 7–8) (C), and blood glucose (D) in ob/ob controls (ob/ob;AgRP-ires-cre and ob/ob;GluN2Bflox/flox) and ob/ob;AgRP-GluN2B KO female mice. (E and F) Body weight (E) and food intake (F) of female mice (9 weeks of age) after implantation of osmotic pumps loaded with leptin (500 ng/h) (9 days). Values in E and F are shown as percent of initial body weight and food intake, respectively. Data are shown as means ± SEM (n = 3–12 mice/group). Repeated measures two-way ANOVA or Student's t test were conducted to evaluate differences between groups. *P ≤ 0.05, **P ≤ 0.01. NS: Not significant.

Mentions: We have reported earlier that exogenous leptin can normalize hyperglycemia in diabetic, obese and leptin-deficient Lepob/ob mice (ob/ob) independently of changes in body weight and caloric intake [7]. This effect of leptin required presence of leptin receptors in AgRP neurons and an intact central melanocortin receptor system. Since NMDARs affect neuronal polarization and activity, we generated ob/ob mice lacking GluN2B subunits in AgRP neurons (ob/ob;AgRP-GluN2B KO) and examined body weight and glucose balance, and tested leptin sensitivity. We found that loss of GluN2B in ob/ob mice did not affect body weight, body composition and food intake (Figure 6A–C), contrasting the lean phenotype of non-ob/ob mice lacking GluN2B in AgRP neurons (Figure 1). Of additional interest, deletion of GluN2B from AgRP neurons in the diabetic ob/ob mice entirely normalized hyperglycemia (Figure 6D). Moreover, in response to exogenous leptin infusion over a 9-day period, ob/ob mice lacking GluN2B subunits in AgRP neurons lost more body weight and exhibited a further reduced food intake relative to ob/ob control animals (Figure 6E and F). Combined, these results show that impaired signaling through GluN2B-NMDARs in AgRP neurons of diabetic and obese mice causes a major improvement in blood glucose control and increases sensitivity to leptin's anti-obesity actions.


The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis.

Üner A, Gonçalves GH, Li W, Porceban M, Caron N, Schönke M, Delpire E, Sakimura K, Bjørbæk C - Mol Metab (2015)

Elimination of GluN2B in AgRP neurons of Lepob/obmice normalizes hyperglycemia independently body weight. (A–D) Body weight (A), body composition (8 weeks of age) (B), average daily food intake (week 7–8) (C), and blood glucose (D) in ob/ob controls (ob/ob;AgRP-ires-cre and ob/ob;GluN2Bflox/flox) and ob/ob;AgRP-GluN2B KO female mice. (E and F) Body weight (E) and food intake (F) of female mice (9 weeks of age) after implantation of osmotic pumps loaded with leptin (500 ng/h) (9 days). Values in E and F are shown as percent of initial body weight and food intake, respectively. Data are shown as means ± SEM (n = 3–12 mice/group). Repeated measures two-way ANOVA or Student's t test were conducted to evaluate differences between groups. *P ≤ 0.05, **P ≤ 0.01. NS: Not significant.
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fig6: Elimination of GluN2B in AgRP neurons of Lepob/obmice normalizes hyperglycemia independently body weight. (A–D) Body weight (A), body composition (8 weeks of age) (B), average daily food intake (week 7–8) (C), and blood glucose (D) in ob/ob controls (ob/ob;AgRP-ires-cre and ob/ob;GluN2Bflox/flox) and ob/ob;AgRP-GluN2B KO female mice. (E and F) Body weight (E) and food intake (F) of female mice (9 weeks of age) after implantation of osmotic pumps loaded with leptin (500 ng/h) (9 days). Values in E and F are shown as percent of initial body weight and food intake, respectively. Data are shown as means ± SEM (n = 3–12 mice/group). Repeated measures two-way ANOVA or Student's t test were conducted to evaluate differences between groups. *P ≤ 0.05, **P ≤ 0.01. NS: Not significant.
Mentions: We have reported earlier that exogenous leptin can normalize hyperglycemia in diabetic, obese and leptin-deficient Lepob/ob mice (ob/ob) independently of changes in body weight and caloric intake [7]. This effect of leptin required presence of leptin receptors in AgRP neurons and an intact central melanocortin receptor system. Since NMDARs affect neuronal polarization and activity, we generated ob/ob mice lacking GluN2B subunits in AgRP neurons (ob/ob;AgRP-GluN2B KO) and examined body weight and glucose balance, and tested leptin sensitivity. We found that loss of GluN2B in ob/ob mice did not affect body weight, body composition and food intake (Figure 6A–C), contrasting the lean phenotype of non-ob/ob mice lacking GluN2B in AgRP neurons (Figure 1). Of additional interest, deletion of GluN2B from AgRP neurons in the diabetic ob/ob mice entirely normalized hyperglycemia (Figure 6D). Moreover, in response to exogenous leptin infusion over a 9-day period, ob/ob mice lacking GluN2B subunits in AgRP neurons lost more body weight and exhibited a further reduced food intake relative to ob/ob control animals (Figure 6E and F). Combined, these results show that impaired signaling through GluN2B-NMDARs in AgRP neurons of diabetic and obese mice causes a major improvement in blood glucose control and increases sensitivity to leptin's anti-obesity actions.

Bottom Line: NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function.We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control.Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

ABSTRACT

Objective: Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown.

Methods: We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies.

Results: We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lep (ob/ob) mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lep (ob/ob) mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions.

Conclusions: GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action.

No MeSH data available.


Related in: MedlinePlus